Continuous process for the preparation of optically pure decahydroisoquinolinecarboxamide

ABSTRACT

The present invention relates to a continuous process for the preparation of [3S-(3α, 4 a β, 8 a β)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide, an intermediate useful in the synthesis of compounds for the treatment of viral diseases, from the reduction of N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide with a noble metal catalyst supported on inorganic oxide carrier in a fixed bed reaction system, with a high optical yield.

TECHNICAL FIELD

The present invention relates to a continuous process for thepreparation of[3S-(3α,4aβ,8aβ)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide fromthe reduction ofN-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide with asupported noble metal catalyst in a fixed bed reaction system.

BACKGROUND ART

[3S-(3α,4aβ,8aβ)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide(hereinafter, refer to as “DHIQ”) is one of the key intermediates in thesynthesis of the compounds useful as antagonists of the excitatory aminoacid receptor or HIV protease inhibitor for the treatment of theacquired immune deficiency syndrome (AIDS).

A process for synthesizngN-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbox amide(hereinafter, refer to as “TICC”) by phosgenation and amination of aphenylalanine derivative is described in U.S. Pat. No. 5,587,481 toDavid R. Allen et al. U.S. Pat. No. 5,587,481 also teaches a method forproducing DHIQ by hydrogenating HCC using 5 wt % Rh/C and/or Rh/aluminacatalysts either in aqueous or organic media at 100° C. and 350 psi.After reaction, the solution should be filtered to remove the catalyst,followed by the removal of the solvent and crystallization to obtainDHIQ. However, under these reaction conditions, the yield of DHIQ isonly 62 to 67% based on TICC because of the low chiroselectivity of therhodium catalysts.

Hoffmann, EPO Application 0 432 695 A2, teaches the use of 5 wt % Rh/Ccatalysts in the reduction of tetrahydroisoquinoline-3-carboxylic acidto [3S-(4aS,8aS)]-decahydroisoquinoline-3-carboxylic acid in acetic acidat 80° C. and 140 atm:

The above reaction was carried out for 24 hours. Racemization occurredand the yield of the desired enantiomer was about 65%.

Sato et al, EPO Application 0 751 128 A1, describes a process forproducing DHIQ from the reduction of TICC with the use of Rh, Pt and Ru.In synthesis example 3, TICC was reduced with a 5 wt % Ru/C catalyst at30 atm and 100° C. for 20 hours. After filtration of the catalyst andsubsequent treatment, the yields of DHIQ primary crystals and secondarycrystals were 52.1% and 20.7%, respectively.

Generally a batch process for the preparation of DHIQ from TICC in theprior art consists of: 1) a powder catalyst is put into a batch reactorequipped with a stirrer and heating/cooling systems; 2) the reactant ina solvent is injected to the reactor; 3) the reactor is closed andpurged with an inert gas; 4) pressurized hydrogen is introduced whileheating the whole content to a desired temperature; 5) hydrogen is cutand reaction is carried out until the pressure drop due to the reductionof the reactant stops; 6) after cooling to room temperature, the productin the solvent is discharged.

As is manifest for those who are skilled in the art, the disadvantagesof the above batch processes are: 1) the process inherently is notproductive and is complicated owing to the adoption of batch reactors;2) it is difficult to precisely control the reaction conditions, forexample, hydrogen partial pressure, because the process is dynamic; 3)it requires a series of post-treatment processes to recover and to reusepowder catalysts; 4) it is in danger of the fire and explosion becausethe catalyst having already reduced is used; and 5) the yield of DHIQ isnot good.

DISCLOSURE OF INVENTION

The intensive and thorough research of the present inventors for solvingthe above problems encountered in prior arts results in the developmentof a new process superior in optical yield.

Therefore, it is an object of the present invention to provide a processfor the preparation of optically active[3S-(3α,4aβ,8aβ)]-N-tert-butyl-decahydro-3-isoquinoline carboxamide, anintermediate useful in the synthesis of compounds for the treatment ofviral diseases, by the continuous reduction ofN-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide with asupported noble metal catalyst in a fixed bed reaction system with ahigh optical yield.

In accordance with an aspect of the present invention, there is provideda method for preparing[3S-(3α,4aβ,8aβ)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide fromN-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide with a highoptical yield, comprising continuously reducingN-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide dissolvedin an organic solvent to[3S-(3α,4aβ,8aβ)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide withhydrogen in a fixed bed reactor charging a noble metal catalystsupported on an inorganic oxide carrier with the range of the metalcontent between 0.5 and 10 wt %, at a temperature in the range of about50 and 200° C., under the pressure in the range of about 300 and 2,500psig and at the WHSV in the range of about 0.1 and 10 h⁻¹, wherein themolecular ratio of hydrogen toN-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide is in therange of about 4 and 10,N-tert-butyl-1,2,3,4-tetrahydro-3(S)isoquinolinecarboxamide content inthe organic solvent is in the range of about 2 and 50 wt % and theinorganic oxide carrier has the BET surface area in the range of about10 and 1,000 m²/g, the median pore diameter of the major pores of lessthan 200 Å and the total pore volume in the range of about 0.2 and 1.2cc/g.

The starting material in the present invention is a carboxamide ofisoquinoline,N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide (TICC),which can be prepared by either a multi-step synthesis process includingphosgenation and amination of a phenylalanine derivative (Allen, D.R.,et al, U.S. Pat. No. 5,587,481) or by any other similar methods (Sato,T., et al., EPO Application 0 751 128 A1). To obtain DHIQ with a highoptical yield, TICC with following specifications is preferred: (1)chromatographic purity by gas chromatography: not less than 99.2%; (2)R(+) enantiomer by chiral HPLC: not more than 1.0%; (3) melting point(range): 92˜100° C.

To achieve a higher space time yield, to reuse the catalyst repeatedlywithout post-treatment steps and to reduce the workup steps, thereaction is performed in a fixed bed reactor in the present invention.There is no limitation in the type of the fixed bed reactor and thedirection of the reactant flow. However, the reaction is preferablycarried out in a trickle-bed type reactor with a down-flow mode of bothhydrocarbon(s) and hydrogen to facilitate the contact between thereactants. The reactor should be equipped with suitable devices toevenly distribute all the reactants.

The reaction should be carried out in a solvent medium to easily pumpTICC into the reactor and to remove the reaction heat easily as thereduction is highly exothermic. Hydrocarbons that do no react withhydrogen and TICC and can dissolve TICC substantially may be used assolvents. As a solvent of the present invention, any type of a singlehydrocarbon or a mixture thereof, e.g., acetic acid, propionic acid,butyric acid, or isobutyric acid, methyl alcohol, ethyl alcohol,n-propyl alcohol, i-propyl alcohol, n-butyl alcohol, sec-butyl alcohol,tert-butyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate,i-propyl acetate, n-butyl acetate, n-hexane, i-hexane, n-heptane,i-heptane, n-octane, or i-octane, can be used. But preferably, n-propylalcohol, i-propyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylacetate, n-butyl acetate, n-hexane, or n-heptane is used. Morepreferably, i-propyl alcohol, tert-butyl alcohol, ethyl acetate, n-butylacetate, n-hexane, or n-heptane is used. Most preferably, ethyl acetate,n-butyl acetate, n-hexane, or n-heptane is used. The concentration ofTICC is 2 to 50 wt % in an organic solution. Preferably theconcentration is 5 to 30 wt %. Depending on the concentration of TICC,the solvent may be heated to dissolve all solid particles. Duringdissolving TICC, TICC solution should not be injected to the reactor. Sotwo TICC dissolving reactors or more should be prepared andalternatively operated in order to provide the reactor with fullydissolved TICC.

TICC can be reduced to DHIQ using molecular hydrogen and a supportednoble metal catalyst. As a support, any inorganic oxide, e.g., alumina,silica, silica-alumina, zirconia, titania, or molecular sieves, issuitable. Among these inorganic materials, alumina and silica arepreferred. The support may have a BET surface area between 10 and 1,000m²/g. Preferably, the BET area of the support is 20 to 500 m²/g and mostpreferably is 50 to 300 m²/g. The pore volume of the support ispreferably 0.2 to 1.2 cc/g, more preferably 0.3 to 1.0 cc/g. There is nolimitation in the pore size distribution of the support, but the supportwith median pore diameter of the major pores of less than 200 angstroms(Å), measured by nitrogen adsorption/desorption, is preferable. Morepreferably the median pore diameter of the support is less than 150 Å.The shape of the support particle may be circular, cylindrical,granular, or in any other form. But to have suitable mechanicalproperties, a pellet of either circular or cylindrical type ispreferred.

As a noble metal, Pd, Pt. Ru, Rh, Os, or a mixture thereof is suitable.Preferably Ru, or Os is used. The concentration of the noble metal(s) ispreferably between 0.5 and 10 wt %, more preferably between 1 and 6 wt%. When the metal content is lower than 0.5 wt %, the activity and theselectivity to DHIQ are low. When the metal content is higher than 10 wt%, the price of metal makes the process uneconomic. The metal issupported onto the support by any suitable method, e.g., incipientwetness impregnation, excess water impregnation, spraying, or mechanicalmixing. After the metal is loaded, the catalyst is calcined in air or inan inert gas atmosphere at a temperature between 300 and 700° C. formore than two hours. Preferably the calcination temperature is 350 to600° C. When the temperature is below 300° C., calcination is incompleteand the precursor compound may not be decomposed. When the temperatureis higher than 700° C., the metal dispersion is too low to have asubstantial catalytic activity. After the catalyst is loaded, thecatalyst should be reduced with flowing hydrogen at a temperaturebetween 50 and 400° C. for at least one hour depending on the metalemployed in the catalyst.

The reduction of TICC to DHIQ is carried out at 300 to 2,500 psig, 50 to200° C., and the weight hourly space velocity (WHSV) of 0.1 to 10 h⁻¹.Preferably DHIQ is prepared at 500 to 2,000 psig, 80 to 170° C., and theWHSV of 0.2 to 6 h⁻¹. More preferably, the reaction is performed at 800to 1,600 psig, 100 to 160° C., and the WHSV of 0.5 to 4 h⁻¹. When thereaction is carried out at a condition out of above ranges, the yield islow and the catalyst deactivates rather rapidly, thus the advantage ofcontinuous reduction disappears.

There is no limitation in the molecular ratio of hydrogen to TICC ifonly it exceeds three to ensure 100% conversion of TICC. However, whenconsidering the economics, the ratio is preferably between 4 and 10.Hydrogen in excess of the reaction stoichiometry may be discharged orrecompressed by recycle compressor and recycled to the reactor.

Reaction products coming out of the reactor is fed to a solventrecovering apparatus where at least apart of solvent is separated fromthe rest of the product. The apparatus can be of any type, e.g., adistillation tower or flash vaporizer. The bottom DHIQ product, or aconcentrate, is sent to a crystallizer. A hydrocarbon solvent, e.g.,hexane or heptane is used during the crystallization.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph illustrating the relationship between yield and timeon stream using a process and catalyst in accordance with the presentinvention.

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples describe the present invention in detail forpurposes of illustration and should not be construed as being limited byprocedures hereafter specified.

PREPARATION EXAMPLE I Preparation of Catalysts

6.35 g of ruthenium chloride (Aldrich, RuCl₃) was dissolved with 40 ccof doubly-distilled water in a 100 cc volumetric flask. Onto 100 g ofNorton SA 3177 alumina (surface area: 100 m²/g; pore volume: 0.49 cc/g;median pore diameter 100 Å), which was in a small tumbler connected to avariable speed motor, the solution containing Ru was evenly sprayedwhile rotating the tumbler at the speed of 50 rpm. After loading themetal, the catalyst was calcined in a muffle furnace at 550° C. for 6hours. The analysis with X-ray fluorescence showed the Ru content of 3.0wt %.

PREPARATION EXAMPLES II˜IV Preparation of Catalysts

All the procedures are similar to those in Preparation Example I exceptfor the use of 100 g of different support materials (TABLE 1).

TABLE I Surface Pore area volume Med. pore diam. Prep. Example No.Support m²/g cc/g Å Prep. Example II Norton 6173 220 0.62 70    Prep.Example III Norton 6176 255 1.14 70/5,000 Prep. Example IV Norton silica144 0.78 80/400  

PREPARATION EXAMPLES V˜VI Preparation of Catalysts

All the procedures are similar to those in Preparation Example I exceptfor the use of corresponding amounts of ruthenium nitrosyl nitrate(Aldrich, 1.5% Ru). As a support, Norton 3177 (Preparation Example V) or6173 (Preparation Example VI) was used, respectively. In these cases,the spraying-drying steps were repeated a few times to have the desiredmetal content of 3 wt %.

EXAMPLE I

Into a 316 stainless steel reactor (2.54 cm ID×60 cm L) on a fullautomatic high pressure reaction system was charged 50 g of catalyst (⅛cylindrical pellet) prepared in Preparation Example I. After a leak testand purging with nitrogen, hydrogen flow of 1 slpm was applied to thereactor while increasing the temperature from room temperature to 300°C. at the rate of 1° C./min. After holding the temperature at 30° C. for2 hours, the reactor was cooled to 150° C. Then 10 wt % TICC in asolvent was pumped to the reactor at a WHSV and pressure specified inTABLE II with a two-fold excess amount of hydrogen. Samples were takenevery 4 hours on steam and analyzed with a FID GC (60 m×0.25 mm×0.25 μmβ-DEX 120 column). All the data specified in TABLE II were taken at 100hours on stream.

TABLE II T P WHSV Conversion Sel. To DHIQ Catalyst ° C. psig H⁻¹ Solvent% % Prep. Example I 110 1350 0.5 butyl acetate 100 96.5 Prep. Example I120 1500 2.0 butyl acetate 99.0 91.0 Prep. Example I 133 1500 3.0 butylacetate 100 92.5 Prep. Example I 145 1350 1.5 butyl acetate 100 95.4Prep. Example I 150 996 0.5 butyl acetate 90.1 91.0 Prep. Example I 150996 0.5 heptane 90.0 89.7 Prep. Example I 150 1350 0.5 butyl acetate96.7 91.5 Prep. Example I 150 1350 1.0 butyl acetate 100 93.3 Prep.Example I 150 1350 1.5 butyl acetate 100 94.4 Prep. Example I 160 15003.0 butyl acetate 100 90.0 Prep. Example II 150  996 0.5 butyl acetate95.3 86.4 Prep. Example III 150  996 0.5 butyl acetate 98.0 86.1 Prep.Example IV 140 1350 1.5 butyl acetate 100 92.6 Prep. Example IV 150  9960.5 butyl acetate 96.3 90.0 Prep. Example IV 150  996 0.5 ethyl acetate95.7 90.5 Prep. Example IV 150 1350 0.5 butyl acetate 97.6 87.1 Prep.Example IV 150 1350 1.5 butyl acetate 100 89.3 Prep. Example V 150  9960.5 butyl acetate 80.0 87.5 Prep. Example VI 150  996 0.5 butyl acetate94.7 86.4 Prep. Example VI 150  996 0.5 i-propanol 95.6 84.5

COMPARATIVE EXAMPLES I˜IV Uncontrolled

Reaction tests were carried out in butyl acetate at 150° C., 996 psig,and the WHSV of 0.5 h⁻¹ in the same manner as in the Example I exceptfor the catalyst employed (TABLE III). The catalyst was the conventionalcommercial catalyst.

TABLE III Comp. Conver- Sel. To Example No. Catalyst sion % DHIQ % Comp.Exam. I Johnson Matthey 2% Ru/C 93.0 67.5 Comp. Exam. II Degussa H257 2%Ru/alumina, 94.9 83.0 Lot: CC4-243 Comp. Exam. III Chemcat 2%Ru/alumina, 77.5 82.5 Lot: 456-67020 Comp. Exam. IV Johnson Matthey 3%Ru/silica 82.8 74.2

EXAMPLE II

The reaction was carried out in a similar reaction system to that inExample I using 150 g of the catalyst prepared by following the methoddescribed in Preparation Example I. 150 g of3% Ru on Norton 3177 aluminawere charged in a fixed bed reactor. After purging with nitrogen andreduction of the catalyst at 300° C., a 10 wt % TICC in butyl acetatesolution was pumped to the reactor at 150° C., 1,350 psig, and the WHSVof 1.0 h⁻¹. During the reaction, the pressure was kept at 1350 psigwhile varying the temperature and WHSV as shown in FIG. 1. FIG. 1 is agraph illustrating the relationship between yield and time on streamusing a process and catalyst in accordance with Example II. As shown inFIG. 1, no deactivation was observed for more than 10 days.

41 liters of butyl acetate solution containing DHIQ (purity 92.2 wt %)were collected after reaction for 200 hours and were put into a 50 literglass reactor equipped with a refrigeration system to get crystals ofDHIQ. After evaporating about 90% of butyl acetate in the solution, 15liters of n-heptane were added into the reactor. Then the reactor wasslowly cooled from 60° C. to −10° C. at a rate of 0.5° C./min. The yieldof the primary crystals was 73%. The procedure was repeated to get thesecondary crystals with the yield of 19%. The optical purity of thecrystals was 99.5%.

Optical rotation: [α]^(D)20=−72.60°; melting point: 114.3° C. (spread112-115° C.)

The yield of the present continuous hydrogenation process is higher thanthat of the prior art batch process such as U.S. Pat. No. 5,587,481(yield: 62-67%) and EPO Application 0 751 128 (primary crystals: 52.1 wt%, secondary crystals: 20.7 wt %).

A number of alternative embodiments and variations will be apparent tothose skilled in the art. Therefore, the aforementioned descriptionshould not be interpreted to limit the invention.

We claim:
 1. A method of preparing[3S-(3α,4aβ,8aβ)]-N-tert-butyl-decahydro-3-isoquinoline carboxamide fromN-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide with a highoptical yield, comprising continuously reducingN-tert-butyl-1,2,3,4tetrahydro-3(S)-isoquinolinecarboxamide dissolved inan inorganic solvent to[3S-(3α,4aβ,8aβ)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide withhydrogen in a fixed bed reactor charging a noble metal catalystsupported on an inorganic oxide carrier with the range of the metalcontent between 0.5 and 10 wt %, at a temperature in the range of about50 and 200° C., under the pressure in the range of about 300 and 2,500psig and at the WHSV in the range of about 0.1 and 10 h⁻¹, wherein themolecular ratio of hydrogen toN-tert-butyl-1,2,3,4tetrahydro-3(S)-isoquinolinecarboxamide is in therange of about 4 and 10,N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide content inan organic solvent is in the range of about 2 and 50 wt % and theinorganic oxide carrier has the BET surface area in the range of about10 and 1,000 m²/g, the median pore diameter of the major pores of lessthan 200 Å and the total pore volume in the range of about 0.2 and 1.2cc/g.
 2. The method of claim 1 wherein the temperature is in the rangeof about 80° C. and 170° C., the pressure is in the range of about 500and 2,000 psig and the WHSV is in the range of about 0.2 and 6 h⁻¹. 3.The method of claim 2 wherein the temperature is in the range of about100° C. and 160° C., the pressure is in the range of about 800 and 1,600psig and the WHSV is in the range of about 0.5 and 4 h⁻¹.
 4. The methodof claim 1 wherein the N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide content in the organic solvent is in the range of about 5and 30 wt %.
 5. The method of claim 1 wherein the organic solvent is atleast one selected from the group consisting of acetic acid, propionicacid, butyric acid, isobutyric acid, methyl alcohol, ethyl alcohol,n-propyl alcohol, i-propyl alcohol, n-butyl alcohol, sec-butyl alcohol,tert-butyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate,i-propyl acetate, n-butyl acetate, n-hexane, i-hexane, n-heptane,i-heptane, n-octane, and i-octane.
 6. The method of claim 5 wherein theorganic solvent is at least one selected from the group of i-propylalcohol, tert-butyl alcohol, ethyl acetate, n-butyl acetate, n-hexane,and n-heptane.
 7. The method of claim 6 wherein the organic solvent isat least one selected from the group of ethyl acetate, n-butyl acetate,n-hexane, and n-heptane.
 8. The method of claim 1 wherein the noblemetal is ruthenium or osmium.
 9. The method of claim 1 wherein the metalcontent is in the range of about 1 and 6 wt %.
 10. The method of claim 1wherein the inorganic oxide carrier is selected from the groupconsisting of alumina, silica, silica-alumina, zirconia, titania, andmolecular sieves.
 11. The method of claim 10 wherein the inorganic oxidecarrier is alumina or silica.
 12. The method of claim 1 wherein the BETsurface area of the inorganic oxide carrier is in the range of about 20and 500 m²/g.
 13. The method of claim 12 wherein the BET surface area ofthe inorganic oxide carrier is in the range of about 50 and 300 m²/g.14. The method of claim 1 wherein the total pore volume of the inorganicoxide carrier is in the range of about 0.3 and 1.0 cc/g.
 15. The methodof claim 1 wherein the fixed bed reactor is a trickle-bed reactor type.